A macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that inhibits random migration of macrophages to inflammatory regions, and plays an important role in systemic/local inflammation and immune responses (Nishihira J., J Interferon Cytokine Res, (2000) 20:751-762; Bucala R., FASEB J (1996)7:19-24).
MIF has been reported to be produced by immunocompetent cells (for example, lymphocytes and macrophages) and a pituitary in response to biological invasion (for example, stimulations by oxidative stress-inducing endotoxin, active oxygen and ultraviolet light), located upstream of inflammatory cytokine cascade, and control inflammatory reactions (by inducing expressions of other inflammatory cytokines) (Annual Reports in Medical Chemistry, Volume 33, Page 24, 1998; Advances in Immunology, Volume 66, Page 197, 1997).
MIF has also been reported to play important roles in various biological reactions; (1) it inhibits the anti inflammatory effect of glucocorticoids to promote the inflammation: (2) it is a T-lymphocyte activation-promoting factor: (3) it inhibits p53 function: and (4) it relates to the proliferation and differentiation of adipocytes and cancer cells (Bucala R., FASEB J (1996)7:19-24; Bernhagen J, et al Nature 365:756-759, 1993; Calandra T, et al Nature 377:68-71, 1995).
However, excessive inflammatory response resulting from excessive production of MIF, which exhibits inflammatory effect, causes many kinds of (inflammation-associated) disorders.
There are various disorders caused by MIF. Representative disorder (disease) is known as a delayed allergy of chronic rheumatoid arthritis (type IV: cellular immune reaction). Recent years, the associated disorders have been widely apparent to cause arteriosclerosis and endometriosis, and the like. Furthermore, it is reported that the concentration of MIF in lung lavage fluid of acute respiratory distress syndrome (ARDS), urine of patients during rejection response who has received kidney transplantation, and serum of patients suffering from acute myocardial infarction, diabetes, systemic lupus erythematosus, Crohn's disease, and atopic dermatitis has risen more significantly than that of healthy person.
In addition, a set of administration of anti-MIF neutralizing antibodies apparently provides effective improvement in pathological animal models with nephritis, hepatitis, pneumonia, arthritis, and endotoxic shock (International Journal of Molecular Medicine, Volume 2, Page 17, 1998).
These studies indicate that the above-described aggravation of pathologies has been attributed to the inflammatory effect of MIF.
The following references report in detail a relationship between MIF and various disorders.    1) Makita H, et al Am J Respir Crit. Care Med 158:573-579, 1998
This reports that lipopolysaccharide (LPS) stimulus to model rats with lung disorder increases mRNA of MIF to infiltrate neutrophil and monocyte into alveoli and induce them into bronchoalveolar lavage fluid, while administration of an anti-MIF antibody before LPS administration decreases the infiltration and induction as well as inhibits breeding in lungs. This result shows that inhibition of MIF activity effectively prevents and treats lung disorders. Furthermore, it shows that the inhibition of MIF activity also effectively treats sepsis since the decrease in platelet was inhibited.    2) Kobayashi S, et al Hepatology 29:1752-1759, 1999
It is confirmed that administration of anti-MIF antibody to rat models with BCG (bacilli Calmette Guerin)-LPS-induced acute hepatitis increased survival rate and inhibited an increase of TNF-α. This indicates that inhibition of MIF activity effectively prevents and treats acute hepatitis.    3) Mikulowaska A, et al J Immunol 1585514-5517, 1997; Ichiyama H, et al Cytokine 26:187-194, 2004
It is reported that inhibition of MIF activity effectively prevents and treats rheumatoid arthritis since administration of anti-MIF antibody in experiments using type II collagen arthritis and adjuvant arthritis model animals inhibits inflammatory response.    4) Donnelly S C, et al Nat Med 3:320-323, 1997
It is confirmed that an increase in inflammatory cytokine was inhibited by administrating anti-MIF antibody to patients with acute respiratory distress syndrome (ARDS). In short, it shows that inhibition of MIF activity effectively prevents and treats acute respiratory distress syndrome (ARDS).    5) Mizue Y, et al Proc. Natl. Acad. Sci. USA 102:14410-14415, 2005
It shows that inhibition of MIF activity effectively prevents and treats bronchial asthma since administration of anti-MIF antibody effectively improved pathology of model rats with bronchial asthma.    6) Yang N, et al Mol Med 4:413-424, 1998; Lan H Y, et al J Exp Med 185:1455-1465, 1997
It shows that inhibition of MIF activity effectively prevents and treats rapidly-progressive-glomerulonephritis since administration of anti-MIF antibody effectively improved pathology of models with rapidly-progressive-glomerulonephritis.    7) Leung J C, et al Nephrol Dial Transplant 19:36-45, 2003
It shows that inhibition of MIF activity effectively prevents and treats IgA nephropathy since administration of anti-MIF antibody effectively improved pathology of models with IgA nephropathy.
As shown above, various disorders closely attribute to MIF, and therefore substances inhibiting the MIF activity are strongly desired to relieve symptoms of such disorders.
Thioredoxin is a 12 kDa multifunctional polypeptide which has oxidoreduction (Redox) activity by disulfide/dithiol exchange reaction between two cysteine residues in an active site sequence: -Cys-Gly-Pro-Cys-, SEQ ID NO: 4 (Redox regulation of cellular activation Ann. Rev. Immunol. 1997; 15:351-369). Thioredoxin has been isolated and identified from many prokaryotes and eukaryotes since it was isolated from Escherichia coli as an important enzyme to synthesize hydrogen ion donor of ribonucleotide reductase and deoxyribonucleotide.
Adult T-cell leukemia derived factor (ADF) is a human thioredoxin which was firstly identified by the inventors of the present invention as an IL-2 receptor inducing factor produced by T-lymphocyte infected with HTLV-1.
Intracellular thioredoxin plays an important role in radical scavenging and controlling transcription factors related to redox, such as activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) (AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1 PNAS. 1997; 94:3633-3638).
Human thioredoxin controls signal transduction of p38 mitogen activating protein kinase (MAPK) and apoptosis signal regulating kinase-1 (ASK-1).
The inventors of the present invention reported that thioredoxin released extracellularly shows cytokine effect or chemokine effect (Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis PNAS. 2001; 98:15143-15148), and that extracellular TRX also moves into cells (Redox-sensing release of thioredoxin from T lymphocytes with negative feedback loops J. Immunol. 2004; 172:442-448).
However, no report has yet shown a relationship between MIF and thioredoxin and a method for screening substances related to MIF.